A case for the study of native extracellular vesicles.

Three main areas of research revolve around extracellular vesicles (EVs): their use as early detection diagnostics for cancer prevention, engineering of EVs or other enveloped viral-like particles for therapeutic purposes and to understand how EVs impact biological processes. When investigating the biology of EVs, it is important to consider strategies able to track and alter EVs directly , as they are released by donor cells. This can be achieved by suitable engineering of EV donor cells, either before implantation or directly Here, we make a case for the study of native EVs, that is, EVs released by cells living within a tissue.

A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan.

Autophagy-lysosomal function is crucial for maintaining healthy lifespan and preventing age-related diseases. The transcription factor TFEB plays a key role in regulating this pathway. Decreased TFEB expression is associated with various age-related disorders, making it a promising therapeutic target.

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration.

Clinical and research updates on the VISTA immune checkpoint: immuno-oncology themes and highlights.

Immune checkpoints limit the activation of the immune system and serve an important homeostatic function but can also restrict immune responses against tumors. Inhibition of specific immune checkpoint proteins such as the B7:CD28 family members programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) has transformed the treatment of various cancers by promoting the anti-tumor activation of immune cells. In contrast to these effects, the V-domain immunoglobulin suppressor of T-cell activation (VISTA) regulates the steady state of the resting immune system and promotes homeostasis by mechanisms distinct from PD-1 and CTLA-4.

Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials.

Ionizing radiation is frequently used to treat solid tumors, as it causes DNA damage and kill cancer cells. However, damaged DNA is repaired involving poly-(ADP-ribose) polymerase-1 (PARP-1) causing resistance to radiation therapy. Thus, PARP-1 represents an important target in multiple cancer types, including prostate cancer.

Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment.

Unlabelled: The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC).

NFE2L2 Mutations Enhance Radioresistance in Head and Neck Cancer by Modulating Intratumoral Myeloid Cells.

Unlabelled: Radiotherapy (RT) is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high-risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone.

Decursin inhibits EGFR-ERK1/2 signaling axis in advanced human prostate carcinoma cells.

We have shown that decursin, a coumarin compound, induces cell cycle arrest and apoptosis in human prostate cancer cells (PCa); however, its molecular mechanisms are largely unexplored. We studied the mechanisms associated with its anticancer activity in advanced human prostate carcinoma cells. We found that decursin inhibited epidermal growth factor receptor (EGFR) signaling by inhibiting its activating phosphorylation at tyrosine 1068 residue in DU145 and 22Rv1 cells.

The Combination of Radiotherapy and Complement C3a Inhibition Potentiates Natural Killer cell Functions Against Pancreatic Cancer.

Pancreatic cancer is one of the deadliest cancers, against which current immunotherapy strategies are not effective. Herein, we analyzed the immune cell composition of the tumor microenvironment of pancreatic cancer samples in The Cancer Genome Atlas and found that the presence of intratumoral NK cells correlates with survival. Subsequent analysis also indicated that NK cell exclusion from the microenvironment is found in a high percentage of clinical pancreatic cancers and in preclinical models of pancreatic cancer.

Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell phenotype.

Adult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures postradiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function.

Y box binding protein 1 inhibition as a targeted therapy for ovarian cancer.

Y box binding protein 1 (YB-1) is a multifunctional protein associated with tumor progression and the emergence of treatment resistance (TR). Here, we report an azopodophyllotoxin small molecule, SU056, that potently inhibits tumor growth and progression via YB-1 inhibition. This YB-1 inhibitor inhibits cell proliferation, resistance to apoptosis in ovarian cancer (OC) cells, and arrests in the G1 phase.

The prevalence of alcohol and other drugs in fatal road crashes in Victoria, Australia.

Background: Driving under the influence of drugs, including alcohol, is a globally recognised risk factor for road traffic crashes. While the prevalence of alcohol and other drugs in fatal road crashes has been examined in other countries, recent data investigating drug driving in fatal Australian crashes are limited. This study aimed to examine how the presence of alcohol and other drugs in fatal road trauma in Victoria has changed over time in different road users.

Patient-specific record linkage between emergency department and hospital admission data for a cohort of people who inject drugs: methodological considerations for frequent presenters.

Background: People who inject drugs (PWID) have been identified as frequent users of emergency department (ED) and hospital inpatient services. The specific challenges of record linkage in cohorts with numerous administrative health records occurring in close proximity are not well understood. Here, we present a method for patient-specific record linkage of ED and hospital admission data for a cohort of PWID.

Ambulance dispatch of older patients following primary and secondary telephone triage in metropolitan Melbourne, Australia: a retrospective cohort study.

Background: Most calls to ambulance result in emergency ambulance dispatch (direct dispatch) following primary telephone triage. Ambulance Victoria uses clinician-led secondary telephone triage for patients identified as low-acuity during primary triage to refer them to alternative care pathways; however, some are returned for ambulance dispatch (secondary dispatch). Older adult patients are frequent users of ambulance services; however, little is known about the appropriateness of subsequent secondary dispatches.

Novel Aza-podophyllotoxin derivative induces oxidative phosphorylation and cell death via AMPK activation in triple-negative breast cancer.

Background: To circumvent Warburg effect, several clinical trials for different cancers are utilising a combinatorial approach using metabolic reprogramming and chemotherapeutic agents including metformin. The majority of these metabolic interventions work via indirectly activating AMP-activated protein kinase (AMPK) to alter cellular metabolism in favour of oxidative phosphorylation over aerobic glycolysis. The effect of these drugs is dependent on glycaemic and insulin conditions.

The role of Glial cell derived neurotrophic factor in head and neck cancer.

Glial cell-derived neurotrophic factor (GDNF) is reported to promote the survival of neurons and salivary gland regeneration after radiation damage. This study investigated the effect of GDNF on cell migration, growth, and response to radiation in preclinical models of head and neck squamous cell carcinoma (HNSCC) and correlated GDNF expression to treatment outcomes in HNSCC patients. Our ultimate goal is to determine whether systemic administration of GDNF at high dose is safe for the management of hyposalivation or xerostomia in HNSCC patients.

Variations in the care of agitated patients in Australia and New Zealand ambulance services.

Objective: The objective of the present study is to examine variations in paramedic care of the agitated patient, including verbal de-escalation, physical restraint and sedation, provided by ambulance services in Australia and New Zealand.

Methods: To examine the care of agitated patients, we first identified and reviewed all clinical practice guidelines for the management of agitated patients in Australian and New Zealand ambulance services between September and November 2018. We then conducted a structured questionnaire to obtain further information on the training, assessment and care of agitated patients by the ambulance services.

Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance.

Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor.

The Immune Subtypes and Landscape of Squamous Cell Carcinoma.

Purpose: To identify immune subtypes and investigate the immune landscape of squamous cell carcinomas (SCC), which share common etiology and histologic features.

Experimental Design: Based on the immune gene expression profiles of 1,368 patients with SCC in the Cancer Genome Atlas (TCGA), we used consensus clustering to identify robust clusters of patients and assessed their reproducibility in an independent pan-SCC cohort of 938 patients. We further applied graph structure learning-based dimensionality reduction to the immune profiles to visualize the distribution of individual patients.

Drug overdose in the ED: a record linkage study examining emergency department ICD-10 coding practices in a cohort of people who inject drugs.

Background: Drug overdose is a leading cause of mortality and morbidity amongst people who inject drugs (PWID). Drug overdose surveillance typically relies on the International Classification of Diseases (ICD-10) coding system, however its real world utilisation and the implications for surveillance have not been well characterised. This study examines the patterns of ICD-10 coding pertaining to drug overdoses within emergency departments for a cohort of known PWID.

Five-year Changes in Methamphetamine Use, Dependence, and Remission in a Community-recruited Cohort.

Objectives: Investigate patterns of methamphetamine use over time, specifically factors associated with remission from dependent and harmful patterns of use; and examine drug treatment and health/support service utilization pathways among people who use methamphetamine.

Methods: People who regularly use methamphetamine were recruited from nontreatment settings in Melbourne, Australia, in 2010, and followed up twice over 5 years. Trajectories of past-month methamphetamine use and methamphetamine dependence were mapped.

Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes.

Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands.

Knowledge of naloxone and take-home naloxone programs among a sample of people who inject drugs in Australia: Variations across capital cities.

Introduction And Aims: Take-home naloxone (THN) programs targeting people who inject drugs (PWID) have been running in some Australian states and territories since 2012. In this study, we aimed to determine the extent to which PWID in the capital cities of all Australian states and territories are aware of naloxone and THN programs, whether awareness of these programs has changed over time.

Design And Methods: Data were obtained from cross-sectional surveys of a total of 2088 PWID conducted annually as part of the Illicit Drug Reporting System from 2013 to 2015.

Are People Who Inject Drugs Frequent Users of Emergency Department Services? A Cohort Study (2008-2013).

Background: Although people who inject drugs (PWID) have been described as frequent users of emergency services, the majority of research is cross-sectional and involves records from a single emergency department (ED).

Objectives: We describe characteristics of state-wide ED presentations in a cohort of PWID, and compare presentation rates to the general population. We also examine characteristics associated with frequent ED use.